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Critical Care Reviews Newsletter

February 24^th 2013

Welcome

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Welcome to the 64th Critical Care Reviews Newsletter, bringing you the best critical care research published in the past week, plus a wide range of free full text review articles and guidelines from over 300 clinical and scientific journals.

This week's research studies include yet more evidence that hydroxyethyl starches are harmful, two studies on the new oral anticoagulants, two studies on coronary revascularization and a phase two study investigating a novel anti-sepsis therapy. There are several editorials and commentaries, including a debate on a potential move to a seven day working week. Amongst the 56 review articles highlighted are three papers on a novel topic, psychiatric emergencies, which could present to the intensivist.

The topic for This Week's Papers is complications of transfusion, starting with a paper on transfusion-related acute lung injury in tomorrow's Paper of the Day.

Research

Journal of the American Medical Association: Hydroxyethyl Starch

To evaluate the association of hydroxyethyl starch use with mortality and acute kidney injury, Zarychanski and colleagues performed a systematic review and meta analysis (initially 38 trials with 10,880 patients, refined to 31 trials with 10,290 after the exclusion of retracted trials) comparing hydroxyethyl starch to crystalloids, albumin, or gelatin. The majority of trials were categorized as having an unclear risk or high risk of bias. Excluding the retracted studies, hydroxyethyl starch was associated with increased mortality (relative risk 1.09; 95% CI 1.02 to 1.17; I² 0%; absolute risk 1.51%; 95% CI 0.02% to 3.00%), increased renal failure among 8725 patients (RR 1.27; 95% CI 1.09 to 1.47; I² 26%; AR 5.45%; 95% CI 0.44% to 10.47%), and increased use of renal replacement therapy among 9258 patients (RR 1.32; 95% CI 1.15 to 1.50; I² 0%; AR 3.12%; 95% CI 0.47% to 5.78%). Conclusion: In a systematic review and meta analysis, hydroxyethyl starch administration was associated with increased risks of death, renal failure and renal replacement therapy.

Abstract: Zarychanski. Association of Hydroxyethyl Starch Administration With Mortality and Acute Kidney Injury in Critically Ill Patients Requiring Volume Resuscitation: A Systematic Review and Meta-analysis. JAMA 2013;309(7):678

New England Journal of Medicine: Dabigatran

In two double-blind, randomized trials, dabigatran (150 mg twice daily) was compared with warfarin (active-control study) or with placebo (placebo-control study) in patients with venous thromboembolism who had completed at least 3 initial months of therapy. In the active-control study, for rates of recurrent venous thromboembolism, dabigatran (1.8%; 26/1430) was not inferior to warfarin (1.3%; 18/1426) (hazard ratio with dabigatran, 1.44; 95% CI 0.78-2.64; P=0.01 for noninferiority). Similarly, there was no difference in major bleeding; dabigatran group (0.9%, 13/1430) versus warfarin group (1.8%; 25/1426) (hazard ratio 0.52; 95% CI 0.27-1.02), although major or clinically relevant bleeding was less frequent with dabigatran (HR 0.54; 95% CI 0.41-0.71). Acute coronary syndromes were more common in the dabigatran group (0.9%; 13/1430) versus (0.2%; 3/1426) (P=0.02). In the placebo-control study, recurrent venous thromboembolism was less common in the dabigatran group (0.4%; 3/681) than in the placebo group (5.6%; 37/662) (HR 0.08; 95% CI 0.02-0.25; P<0.001). Major or clinically relevant bleeding occurred more frequently in the dabigatran group (5.3%; 36/681) versus (1.8%; 12/662) (HR 2.92; 95% CI 1.52 to 5.60). Acute coronary syndromes occurred in 1 patient each in the dabigatran and placebo groups. Conclusion: Dabigatran was not inferior to warfarin for the extended treatment of venous thromboembolism and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo.

Abstract: Schulman. Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism (RE-MEDY and the RE-SONATE Trials). N Engl J Med 2013;368:709-718

New England Journal of Medicine: Apixiban

Agnelli et al completed a randomized, double-blind study, comparing two doses of apixaban (2.5 mg and 5 mg, twice daily for 12 months) with placebo in 2486 patients with venous thromboembolism who had completed 6 to 12 months of anticoagulation therapy. Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 8.8% (73/829) in those receiving placebo, 1.7% (14/840) in those receiving apixaban 2.5 mg (a difference of 7.2%; 95% CI 5.0 to 9.3) and 1.7% (14/813) in those receiving 5 mg of apixaban (a difference of 7.0%; 95% CI, 4.9 to 9.1) (P<0.001 for both comparisons). The rates of major bleeding were 0.5% in the placebo group, 0.2% in the 2.5-mg apixaban group, and 0.1% in the 5-mg apixaban group. The rates of clinically relevant nonmajor bleeding were 2.3% in the placebo group, 3.0% in the 2.5-mg apixaban group, and 4.2% in the 5-mg apixaban group. The rate of death from any cause was 1.7% in the placebo group, as compared with 0.8% in the 2.5-mg apixaban group and 0.5% in the 5-mg apixaban group. Conclusions: Extended anticoagulation with apixaban, at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg), reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding.

Abstract: Agnelli. Apixaban for Extended Treatment of Venous Thromboembolism. N Engl J Med 2013;368:699-708

The Lancet: Coronary Revascularization

Mohr et al report the 5-year results of the multi-centre, randomized SYNTAX trial, which compared coronary artery bypass graft surgery (CABG) with percutaneous coronary intervention (PCI) for the treatment of patients with left main coronary disease or three-vessel disease. 1800 patients were randomly assigned to CABG (n=897) or PCI (n=903). Kaplan-Meier estimates of the major endpoint, a composite rate of major adverse cardiac and cerebrovascular events, were higher in the PCI group (37.3 versus 26·9%, p<0·0001). Likewise, estimates of myocardial infarction ( 9·7% versus 3·8%; p<0·0001) and repeat revascularisation (25·9% versus 13·7% vs ; p<0·0001) were significantly increased with PCI versus CABG. Neither all-cause death (PCI group 13·9% versus CABG group 11·4%; p=0·10) nor stroke (PCI group 2.4% versus CABG group 3·7%; p=0·09) were significantly different. In patients with intermediate or high SYNTAX scores, major adverse cardiac and cerebrovascular events was significantly increased with PCI (intermediate score, PCI group 36·0% versus CABG group 25·8%, p=0·008; high score, PCI group 44·0% versus CABG group 26·8%; p<0·0001). Conclusion: CABG is superior to PCI for complex lesions (high or intermediate SYNTAX scores), although for less complex disease (low SYNTAX scores) or left main coronary disease (low or intermediate SYNTAX scores), PCI is an acceptable alternative.

Abstract: Mohr. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013;381(9867):629-638

Critical Care Medicine: Sepsis

Guntupalli et al completed a prospective, randomized, double-blind, placebo-controlled, multicenter phase 2 trial, investigating whether enteral lactoferrin (talactoferrin), a glycoprotein with anti-infective and anti-inflammatory properties which contributes to gastrointestinal mucosal barrier integrity, could reduce 28-day all-cause mortality in 194 patients with severe sepsis. The all-cause mortality at 28 days was 26.9% in the placebo group and 14.4% in the talactoferrin group (two-sided p = 0.052), representing a 12.5% absolute and a 46.5% relative reduction in mortality, meeting the protocol-specified primary endpoint. Reduction in all cause mortality was sustained at 6 months (p = 0.039). These reductions in mortality were observed across a wide spectrum of subgroups. The drug was well tolerated with a safety profile similar to that of placebo. Conclusion: Enteral administration of talactoferrin reduced 28-day all-cause mortality in patients with severe sepsis.

Abstract: Guntupalli. A Phase 2 Randomized, Double-Blind, Placebo–Controlled Study of the Safety and Efficacy of Talactoferrin in Patients With Severe Sepsis. Critical Care Medicine 2013;41(3):706-716

JACC Cardiovascular Interventions: PCI post Acute Myocardial Infarction with Cardiac Arrest

Mylotte et al conducted a multicenter prospective observational study to assess the impact of multivessel (MV) primary percutaneous coronary intervention (PCI) on clinical outcomes in 266 patients with ST-segment elevation myocardial infarction (STEMI) presenting with cardiogenic shock and resuscitated cardiac arrest.Patients with single vessel disease (SVD, 36.5%) had increased 6-month survival compared to those with multi-vessel disease (MVD, 29.6% vs. 42.3%, p = 0.032). Baseline characteristics were similar in those with MVD undergoing culprit-only (60.9%) or MV (39.1%) primary PCI. However, 6-month survival was significantly greater in patients who underwent MV PCI (43.9% vs. 20.4%, p = 0.0017). This survival advantage was mediated by a reduction in the composite of recurrent cardiac arrest and death due to shock (p = 0.024) in MV PCI patients. In those with MVD, culprit artery PCI success (hazard ratio 0.63; 95% CI 0.41 to 0.96, p = 0.030) and MV primary PCI (HR 0.57; 95% CI: 0.38 to 0.84, p = 0.005) were associated with increased 6-month survival. Conclusion: Multivessel primary PCI may improve outcomes in patients with STEMI and multivessel disease presenting with cardiogenic shock and cardiac arrest.

Full Text:Mylotte. Primary Percutaneous Coronary Intervention in Patients With Acute Myocardial Infarction, Resuscitated Cardiac Arrest, and Cardiogenic ShockThe Role of Primary Multivessel Revascularization. J Am Coll Cardiol Intv 2013;6(2):115-125

Editorial: Kern. ST-Segment Elevation Myocardial Infarction, Cardiac Arrest, and Cardiogenic ShockAn Interventional Triumvirate of Opportunity. J Am Coll Cardiol Intv 2013;6(2):126-127